In this grant proposal the Center for Proteomics and Bioinformatics (CPB) will acquire, install, and operate an Orbitrap Fusion Lumos Tribrid Mass Spectrometer (MS) and ultra high pressure liquid chromatography system optimal for a wide range of structural proteomics, proteome expression, and phosphoproteomics studies. The CPB has assembled a robust research base for the use of this instrument that includes 34 funded projects with 33 PIs/Co-Is who have over $13M of direct costs funding per year in their peer-reviewed grants. These research teams have extensive prior experience with the CPB and the user group has an exemplary record overall in the proteomics field. The Center also operates proteomics core for the Case Center for AIDS Research and the Case Cancer Center both of which are peer-reviewed Cores of major funded NIH funded Centers. The PI and CPB faculty and staff have long-standing experience with installing and operating advanced MS instrumentation assuring that the proposed instrument will have excellent stewardship and that allocations of instrument time will be fair and transparent resulting in a high level of productivity for the research base in Cleveland and across the US including outreach to under represented groups in science. The CPB?s overall MS-based analytical portfolio is very diverse, providing cutting edge technologies to users across the university and beyond spanning small molecule, structural, and quantitative proteomics. For example, last year the CPB supported 55 different user groups carrying out 141 experiments. These users spanned 15 University and Hospital departments (CC & UH) along with outside users, such as industry (7%) or other local or national universities (15%). As user needs have evolved there is increasing demand for higher resolution, higher sensitivity, and higher mass accuracy mass spectrometry (MS) for structural proteomics and other quantitative proteomics studies (particularly phosphoproteomics) that require identification and quantification of peptides modified at specific side chains. Unfortunately, the current high resolution instruments in the Core lack fast duty cycles and ultra-efficient ion optics now available for detection of low abundance species along with innovations like higher energy collisional dissociation (HCD) for accurate assessment of post translational modifications (for phosphoproteomics) and chemical modifications of side chains observed for footprinting. The Core currently utilizes 2 Thermo Elite Orbitrap mass spectrometers coupled to Nano-Acquity ultra high-pressure liquid chromatography systems (UPLC) for these quantitative and structural proteomics studies. Thus, the existing pipelines would have considerably improved performance as well as critical additional capacity in the context of the new instrument.